Dissecting modular synthases through inhibition: A complementary chemical and genetic approach.

Bacterial Proteins / metabolism Peptide Synthases / chemistry Transferases (Other Substituted Phosphate Groups) / metabolism
BpsA Domain-specific inhibitors Indigoidine Natural products Non-ribosomal peptide synthetase

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
15 01 2020
Historique:
received: 29 08 2019
revised: 08 11 2019
accepted: 09 11 2019
pubmed: 10 12 2019
medline: 17 2 2021
entrez: 9 12 2019
Statut: ppublish

Résumé

Modular synthases, such as fatty acid, polyketide, and non-ribosomal peptide synthases (NRPSs), are sophisticated machineries essential in both primary and secondary metabolism. Various techniques have been developed to understand their genetic background and enzymatic abilities. However, uncovering the actual biosynthetic pathways remains challenging. Herein, we demonstrate a pipeline to study an assembly line synthase by interrogating the enzymatic function of each individual enzymatic domain of BpsA, a NRPS that produces the blue 3,3'-bipyridyl pigment indigoidine. Specific inhibitors for each biosynthetic domain of BpsA were obtained or synthesized, and the enzymatic performance of BpsA upon addition of each inhibitor was monitored by pigment development in vitro and in living bacteria. The results were verified using genetic mutants to inactivate each domain. Finally, the results complemented the currently proposed biosynthetic pathway of BpsA.

Identifiants

DOI: 10.1016/j.bmcl.2019.126820 PMID: 31812466
pubmed: 31812466
pii: S0960-894X(19)30789-9
doi: 10.1016/j.bmcl.2019.126820
pii:
doi:

Substances chimiques

Bacterial Proteins 0
Transferases (Other Substituted Phosphate Groups) EC 2.7.8.-
Peptide Synthases EC 6.3.2.-
non-ribosomal peptide synthase EC 6.3.2.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

126820

Subventions

Organisme : Howard Hughes Medical Institute
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Christopher R Vickery (CR)

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Ian P McCulloch (IP)

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.

Eva C Sonnenschein (EC)

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.

Joris Beld (J)

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.

Joseph P Noel (JP)

Howard Hughes Medical Institute, The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Michael D Burkart (MD)

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA. Electronic address: mburkart@ucsd.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › Dissecting modular synthases through...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Carbon-nitrogen ligases › Amino-acid ligases › Dissecting modular synthases through...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Transferases (other substituted phosphate groups) › Dissecting modular synthases through...